CORE D: Abstract The purpose of The Cells and Circuits Core is to provide investigators with tools needed to understand the cellular and physiological basis of intellectual and developmental disabilities (IDDs) and the role of potential therapeutics in IDD biology. Electrophysiological assessment is a vital to the understanding of both cellular and circuit alterations in models of IDD and cell culture is a vital tool in the understanding of cellular and molecular basis of ID. The core will consist of two components, the Neurophysiological Assessment component and the Cellular and Organoid Modeling component. In the Neurophysiological Assessment component, we will provide functional assessments at the cellular, circuit and systems level. The use of state-of-the-art electrophysiological approaches will aid IDDRC investigators in uncovering and understanding basic mechanisms causing the disorders being studied. These electrophysiological approaches consist of experiments performed in brain slices, acutely isolated neurons or cultures providing functional analyses of changes in neurons, local circuits and microcircuits induced primarily by genetic alterations in cellular, mouse or rat models. New techniques include optogenetics, EEG and local field potential (LFP) recording in vivo, and the use of miniscopes to image neuronal calcium transients in freely-behaving rodents to permit and facilitate analyses of developmental neurological functions at the cellular, circuit, and systems levels. In the Cellular and Organoid Modeling component, we will develop and provide models of IDD using human pluripotent stem cells, tissue-derived neural stem cells, and three-dimensional organoid cultures. Because human central nervous system cells are inherently different from rodent cells, we developed the facilities and capabilities to propagate and distribute them 2 cycles ago. In the previous cycle, we expanded the human cell core greatly, with a focus on pluripotent stem cell-derived cultures, including building the basis for the study of human cerebral organoids. We continue to provide these tools and expand our ability to deliver cells and expertise to ID researchers serving as a proxy to estimate neuronal activity in more ethological conditions. The use of stem cell technology provides a novel approach to modeling disease and developing rationale therapies based on utilization of human cells. The Core will provide facilities and expertise to propagate human embryonic stem cells (hESCs), induced pluripotent stem cells (hiPSCs), neural stem and progenitor and other cerebral cell types to create and study cellular models of IDD. A major function of the Core will be to aid investigators in culturing and studying cerebral organoids derived from hESCs and hiPSCs. In addition to its training and service functions, the Core will continue to develop novel methodologies in physiological assessment and human cell culture and analysis. The two components of the Core will interact seamlessly. The Core will interact regularly with the other Cores of the IDDRC and with the Research Project and will also aid investigators in drug discovery and development through interactions with Molecular Screening Shared Resource in the Broad Stem Cell Research and Jonsson Comprehensive Cancer Centers.